One contemporary strategy to cure specific cancers is to identify small molecule drugs that are far more toxic to cancer cells than to normal cells. Chemicals of this type must have specific targets in biochemical pathways that are more critical for the survival of cancer cells than for normal cells. A rich source of materials that have specific mechanisms of toxicity are secondary metabolites (natural products) that have been selected by evolution to be toxic to certain organisms and not others. This project seeks to identify the molecular targets for four natural products known to have patterns of differential cytotoxic activity against human tumor cell lines - suggesting that they may be useful as anti-cancer drugs or drug leads. It is likely that these compounds will have different targets in different metabolic pathways. Project members have achieved the total synthesis of several macrocyclic salicylates and halomon. A total synthesis of diazonamide A and of (sic) is rapidly approaching completion. Efforts to synthesize pelorusides are proposed. We will identify the molecular targets of these compounds in animal cells and determine their function. These efforts will resolve the precise mechanisms of toxicity induced by these small molecules, thereby helping in a substantive way to either validate of (sic) invalidate their potential use in chemotherapy.